title: The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific.
abstract: BACKGROUND
  Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT.
  
  
  METHODS
  A total of four human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild-type AR), and VCaP (wild-type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes.
  
  
  RESULTS
  Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited.
  
  
  CONCLUSIONS
  The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Rishi Raj
authors.initials: RR
authors.lastname: Chhipa
authors.forename: Danny
authors.initials: D
authors.lastname: Halim
authors.forename: Jinrong
authors.initials: J
authors.lastname: Cheng
authors.forename: Huan Yi
authors.initials: HY
authors.lastname: Zhang
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.forename: Clement
authors.initials: C
authors.lastname: Ip
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D002417:Cattle; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000378:metabolism*; D000068538:Dutasteride; D018120:Finasteride / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D058891:5-alpha Reductase Inhibitors; C410798:AR protein, human; D001378:Azasteroids; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D018120:Finasteride; D000068538:Dutasteride
keywords: androgen receptor signaling; antiandrogen; dutasteride; finasteride; prostate cancer